Dedifferentiation is defined as the progression of cells from a more differentiated to a less differentiated state. It is observed in organ regeneration, cancer, asthma, and heart disease and has been linked to stem cell-related processes as well. Dedifferentiation is difficult to study in animals because of paucity in genetically tractable systems. Until recently it was not even clear whether dedifferentiation was regulated by dedicated orderly mechanisms or merely a stochastic, wholesale loss of developmental properties. This question is critical because regulated processes are more accessible to investigation than stochastic ones. Recent work in Dictyostelium, Drosophila and rats showed that dedifferentiation is a regulated process, opening the field to methodical genetic investigation. Studying the basics of Dictyostelium dedifferentiation might implicate homologous mechanisms in other eukaryotes. The proposed project will investigate the genetic basis of Dictyostelium dedifferentiation through genetic screens. This is a high-risk/high-gain proposal, but the risk is conceptual rather than technical. The investigators have already performed pilot genetic screens that yielded interesting mutants, so the technology works well. The nature and generality of the genes and mechanisms that would be found remains to be determined, but the gain might be enormous. Identification of relevant mechanisms would revolutionize the field by providing molecular targets for research and therapy of dedifferentiation-related disorders. Dedifferentiation is involved in human diseases such as cancer, asthma, and heart disease. It is also related to processes involved in adult stem cell renewal. Studying the basics of Dictyostelium dedifferentiation is expected to implicate homologous mechanisms in humans. Identification of relevant mechanisms would revolutionize the field by providing molecular targets for research and therapy of dedifferentiation-related disorders. [unreadable] [unreadable] [unreadable] [unreadable]